The invention relates to absorbent articles such as diapers, training pants, adult incontinence briefs, feminine hygiene products, and the like. In particular, the absorbent articles of the invention contain fecal protease inhibitors and are useful for the prevention and treatment of diaper rash.
Diaper rash is a common form of irritation and inflammation of those parts of an infant's body normally covered by a diaper. This condition is also referred to as diaper dermatitis, napkin dermatitis, napkin rash and nappy rash. While certainly more common in infants, this condition is not, in fact, limited to infants. Any individual who suffers from incontinence to the extent that the use of absorbent articles is required may develop this condition. Susceptible individuals range from newborns, to the elderly, to critically ill, to nonambulatory individuals.
Many types of disposable absorbent products, such as diapers, training pants, adult incontinence devices, sanitary napkins, panty liners, and the like, are available that have a high capacity for absorbing urine and other body exudates. Disposable products of this type generally comprise some sort of liquid-pervious topsheet material, an absorbent core, and a liquid-impervious backsheet material. Although these types of absorbent structures may be highly efficient for the absorption of liquids, it is well recognized that long-term wear of such absorbent articles may compromise the underlying skin in terms of overhydration or exposure to skin irritants commonly found in body exudates. Part 21, Section 333.503 of the Code of Federal Regulations defines diaper rash as “[a]n inflammatory skin condition in the diaper area (perineum, buttocks, lower abdomen, and inner thighs) caused by one or more of the following factors: moisture, occlusion, chafing, continued contact with urine or feces or both, or mechanical or chemical irritation.” It is generally accepted by the medical profession that true diaper rash or diaper dermatitis is a condition which is, in its most simple stages, a contact irritant dermatitis resulting from extended contact of the skin with urine, or feces, or both. Among the most commonly accepted factors linked to diaper rash are ammonia, fecal enzymes, bacteria, the products of bacterial action, urine pH, and Candida albicans. 
As discussed in Buckingham, U.S. Pat. No. 4,556,560; Zimmerer, U.S. Pat. No. 4,657,537; Berg and Stewart, U.S. Pat. No. 4,685,909; Jordan and Ryan, U.S. Pat. No. 4,842,593; Andersen et al. (Contact Dermatitis 30:152-158, 1994); MacFarlane et al. (J. Appl. Bacteriol. 64:37-46, 1988); and Buckingham and Berg, (Pediatric Dermatology 3:107-112, 1986), there is evidence that fecal proteolytic and lipolytic enzymes, of intestinal and/or pancreatic origin, play a direct role in causing the skin irritation and inflammation of diaper rash. Studies with inhibitors designed to inhibit the enzymatic activity of various classes of proteases showed that serine proteases, cysteine proteases and metalloproteases were the most likely to be responsible for the overall proteolytic activity of feces. It is known that the serine proteases trypsin and chymotrypsin, in particular, are nearly always present in grossly measurable quantities in the stools of normal young children, and smaller but detectable quantities are present in normal adult stools.
The irritating effects of fecal enzymatic activity toward the skin are likely to be amplified if urine is present and/or if the skin is occluded. The production of ammonium hydroxide by the action of the bacterial enzyme urease on urine results in an increase in pH, for example to levels of 7.0 and above, at which the enzymatic activity of proteases and other enzymes such as lipases present in feces is enhanced. For example, the optimal pH range for urease activity is 6.4-6.9, for trypsin 7.8 to 8.2, and for lipases 7.5-9.5. At a pH greater than 7.0, free ammonia is released from urine as a toxic additional skin irritant. Urine itself can also contribute to diaper rash by adding moisture to the diaper environment. Water, and particularly water in the form of urine, is especially effective at diminishing the barrier property of skin, thereby enhancing the susceptibility of skin to fecal enzyme irritation. Since urine and feces are commonly present in the absorbent article at the same time, and exposure to the skin for several hours is not uncommon, suitable conditions and ample time are available for this interaction and the resulting skin damage to occur. An alkaline feces pH is a further contributing factor to enhanced enzymatic activity of feces. For example, it is well known that although the feces of breast-fed babies are usually acidic, the feces of bottle-fed and spoon-fed infants are generally alkaline, with a pH ranging from slightly alkaline (pH 7.2-7.5) to very alkaline (pH 8.7 and above). Thus bottle-fed and spoon-fed infants in particular may have a propensity to develop diaper rash due to pH-enhanced activity of fecal enzymes.
In view of the foregoing proposed causes of diaper rash, many approaches have been taken in an attempt to reduce or prevent its occurrence. Many of the most practical approaches attempt to address multiple causes or important cofactors. Reducing skin hydration by frequent changing of diapers, the use of moisture absorbing powders, the use of superabsorbent materials, and improving air flow in diapers are well known approaches. The use of artificial barriers is also widely practiced. Typical of these is the use of a topical cream, ointment, lotion or paste to provide some degree of physical barrier protection to the skin against fecal or urine irritants, regardless of their specific nature. However, the barrier approach, while reducing access of irritants to the skin, may be occlusive in itself and can be aesthetically unpleasing.
In another approach, attempts have been made to maintain skin pH by the use of pH control agents, such as buffering agents or acidic ammonia-neutralizing agents, in an absorbent article or as ingredients in topically applied skin care products. It is thought that effectively maintaining skin pH in its natural acidic state (i.e., about 3.0 to about 5.5) may counteract the irritating effects of ammonia and reduce the activity of fecal enzymes. Reducing the enzymatic activity on the skin by this approach, however, is potentially difficult in the situation where alkaline feces are deposited directly on the skin following a bowel movement.
Certain anti-enzyme compounds have been included in topically applied compositions for treatment or prevention of diaper rash caused by the prolonged contact of human skin with body wastes. For example, U.S. Pat. No. 4,556,560 describes compositions containing water-soluble lipase inhibitors that are preferably metallic salts such as zinc chloride in a barrier-like carrier such as polyethylene glycol. U.S. Pat. No. 5,091,193 describes compositions for application to the skin at the time of diaper change that contain a chelating agent such as phytic acid, ethylenediamine tetraacetic acid, (EDTA) and the like, that restricts the availability of metals that ureases and proteases require as cofactors for activity. The composition may further include a lipase inhibitor such as an ester of a fatty alcohol or an additional anti-enzyme, such as a saturated or unsaturated, linear or branched zinc salt of a fatty acid of 2 to 22 carbon atoms or an aminated acylated acid such as propionylcysteine, propionylhydroxyproline or caproylcysteine. Cleaning wipes having skin cleaner compositions that incorporate protease inhibitors have also been described for use in place of toilet paper for cleansing body excreta from the skin to prevent irritation.
Although there appear to be multiple factors involved in the development of diaper rash, it is likely that the physiological responses of the skin to irritants such as fecal enzymes, ammonia, and the like, may involve some common mechanisms. For example, it is known that the production of cytokines by skin cells is a common response to the presence of irritants and to perturbation of the outer barrier layer of the skin (the stratum corneum). The principal cell type that appears to be involved in the production of cytokines is the keratinocyte, which is the cell type found directly beneath the stratum corneum and is the most likely to initially encounter an irritant. It has been demonstrated that the keratinocyte secretes a wide variety of different cytokines, including the proinflammatory cytokine interleukin 1-alpha (IL-1α), in response to irritants. This cytokine and others induce a cascade of events which may eventually lead to the physiological appearance of erythema, papules, scaling and ulceration which are collectively described as diaper dermatitis.
While compositions for the treatment or prevention of diaper rash have been described that include certain inhibitors of urease, lipase and/or protease enzyme activity, it has not been previously recognized that fecal proteases play an important role in inducing the initial cytokine response of keratinocytes leading to the inflammatory response cascade and that the inhibition of proteases, in particular, provides a more specific means of preventing or treating diaper rash than previously disclosed. In particular, there has been no previous description of a treatment regimen for the reduction or prevention of diaper dermatitis by which protease inhibitors are incorporated directly into absorbent articles such as diapers and the like, or that effective amounts of the protease inhibitors may be delivered automatically to a wearer's skin from the treated articles without manual intervention. Further, it has not been previously recognized that the use, preferably the repeated use, of treated absorbent articles may automatically transfer sufficient levels of the protease inhibitors to selected regions of the wearer's skin to provide a proactive defense against fecal protease penetration and activity.